Project 4: Abstract Project 4, a biomedical project, is an integral component of the Dartmouth Superfund Research Program. Over the past 18 years, we designed and tested methods of measuring environmentally relevant levels of exposure to metals and applied novel biomarkers of exposure, susceptibility, and early response to large- scaled, population-based epidemiologic studies in the US. To date, we have tested over 8,000 households for arsenic (As), of which over 3,500 had private water systems. A GIS analysis of the data (performed in collaboration with the Trace Element Analysis Core) revealed distinct clusters of high household water As levels. Over the past five years, we successfully established a pregnancy cohort of women who use private wells in one of these cluster regions. Of the household tap water samples tested thus far, ~15% exceeded the maximum contaminant level for As established by the US EPA of 10 ?g/L. Over the next five years, we will begin recruitment in another cluster region that is adjacent to planned and existing Superfund sites. While evidence suggests that As is related to adult onset diabetes and hypertension, its effects on these outcomes during pregnancy are uncertain. Thus, we will determine whether As influences glucose and blood pressure control during pregnancy and identify potential genetic susceptibility loci for these effects. Additionally, we will test pregnant women and newborns for markers of systemic inflammation and vascular endothelial dysfunction that have been previously found to relate to As exposure among adults in more highly exposed regions. Our hypothesis is that pregnancy and fetal development represent windows of susceptibility to the effects of As on cardiometabolic outcomes. To our knowledge, our study is one of the only molecular epidemiologic investigations of pregnancy and early life exposure to As in vulnerable subgroups of the general population of the US. Cardiovascular disease is the leading cause of morbidity and mortality worldwide, and the risk for this disease begins early in life. Thus, we are now positioned to capitalize upon our work in the previous grant period to fill critical gaps in our understanding of the lifelong health impacts of early life exposure to As, one of the leading environmental chemicals of concern.